2'-Nitroflavone targets PARP1 and alters cytoskeleton to inhibit triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is an aggressive subtype, often resistant to chemotherapy. Flavonoids are polyphenolic compounds that exhibit anticancer properties. In this study, the potential antitumor effects of the synthetic flavonoid 2'-nitroflavone (2'NF) in TNBC were investigated. Our in vitro results show that 2'NF reduces TNBC cell viability, proliferation, and survival, while inducing cell cycle arrest, apoptosis, and mitotic catastrophe. Additionally, 2'NF inhibits TNBC and endothelial cell migration, likely due to severe disruptions in tubulin and actin cytoskeletons. Computational analysis revealed that 2'NF has a favorable pharmacological profile as a potential drug candidate. In a murine TNBC model, 2'NF administration slowed tumor growth without evident toxicity. Mechanistic in silico studies propose that poly(ADP-ribose) polymerase-1 (PARP1), a key enzyme involved in DNA repair, may be a target of 2'NF. Molecular docking and dynamics simulations demonstrated the formation of a thermodynamically stable complex between 2'NF and the catalytic domain of PARP1. Moreover, in vitro PARP enzymatic activity was inhibited by 2'NF in TNBC cells. These promising findings suggest the potential of 2'NF as a novel PARP1 inhibitor or a scaffold for developing improved inhibitors, offering new avenues for combination therapies in TNBC treatment.